US5880106A - Oral dosing formulations of dideoxy purine nucleosides - Google Patents

Oral dosing formulations of dideoxy purine nucleosides Download PDF

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US5880106A
US5880106A US08/942,660 US94266097A US5880106A US 5880106 A US5880106 A US 5880106A US 94266097 A US94266097 A US 94266097A US 5880106 A US5880106 A US 5880106A
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magnesium
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ddi
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Ismat Ullah
Shreeram Narahari Agharkar
Gary James Wiley
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Bristol Myers Squibb Co
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/08—Oxides; Hydroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/12—Magnesium silicate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/42—Phosphorus; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • This invention relates to pharmaceutical compositions which provide convenient, palatable oral dosage formulations for the acid-labile dideoxy purine nucleosides such as 2',3'-dideoxyadinosine, 2'3'-dideoxyinosine, and 2',3'-dideoxyguanosine. More specifically, it relates to inclusion of specific antacid buffers which confer special advantages such as increased bioavailability, lower variability in bioavailability between patients, greater convenience, lessened potential for gastrointestinal distress, and higher patient acceptability.
  • compositions containing 2',3'-dideoxyadenosine (ddA), 2'3'-dideoxyinosine (ddI), and 2'3'-dideoxyguanosine (ddG), and their triphosphates for treating retroviral infections have been disclosed.
  • Mitsuya, et al., in U.S. Pat. No. 4,861,759 disclose the oral administration of these dideoxy purine nucleosides in the form of liquids or tablets containing antacid buffering agents so that the pH of the resultant composition is in the neutral (pH 6-pH 8) range.
  • an oral gavage formulation containing 0.1N acetate buffer with a pH of 6.8 to 7.2. Enteric coating of the tablets is also disclosed as an option.
  • enteric coatings tended to reduce the nucleoside drug's bioavailability and depress peak plasma levels. High peak plasma levels of active drug are an important requirement for its clinical antiviral activity. Enteric coated formulations also were especially susceptible to a meal effect, further reducing bioavailability.
  • citrate-phosphate buffered ddI formulations which allow oral dosing, were preferred clinically for long-term therapy over the earlier available lyophilized dosage form of the drug which requires reconstitution prior to intravenous administration.
  • These oral powder formulations for reconstitution consist of varying ddI levels combined with the same amount of buffering ingredients (about 10 g per day) regardless of final drug dose strength. All dose strength formulations thus have the same acid neutralization capacity.
  • the powder blend sachets are bulky (about 20 g/dose) and inconvenient - their use causes some patient inconvenience. Reconstitution is always required prior to administration and results in a large volume of constituted solution (due to 20 g of solute) to be ingested. This salty solution can cause diarrhea and the required ingestion of about 10 g per day of soluble antacid buffers may result in systemic alkalosis when administered on a long-term basis as required, for example, in treating HIV infections.
  • compositions for these acid-labile nucleoside derivatives which would allow convenient oral administration of reduced mass dosage formulations such as tablets which could be chewed and swallowed or readily dispersed in liquid for ingestion.
  • Such a composition would also allow formulation of reduced mass sachet dosage forms.
  • Another objective was to find a combination of antacid buffers effective in preventing acid hydrolysis of the nucleosidic agent but whose effect on diarrhea and/or electrolyte and pH imbalances would be minimized.
  • a further object of the invention was to provide a pleasant tasting composition with high levels of patient acceptance and tolerability.
  • a key to realization of these objects was in providing in a reduced mass form the same amount of bioavailable drug delivered by the bulky dry powder blend provided in the citrate-phosphate buffer sachets.
  • improved buffer systems comprising certain water-insoluble aluminum or calcium carbonates in combination with water-insoluble magnesium antacids were found to increase drug bioavailability by about 20 to 25%. Addition of reduced amounts of compatible sweetening and flavoring agents for incorporation into the improved drug-buffer composition also contributed to achieving the objects of the invention.
  • compositions which allow the oral administration of the acid-labile dideoxy purine nucleoside derivatives in the form of reduced mass powder sachets and preferably as convenient palatable oral tablets. These tablets are also readily dispersible in liquids to offer an optional route of ingestion.
  • the crux of the present invention lies in the unobvious selection of certain water-insoluble antacids to provide the unique buffering action, allowing reduced mass of the formulation while providing increased bioavailability, enhanced palatability and decreased gastrointestinal side-effects.
  • FIG. 1 discloses a semi-logithmic plot of the degradation of Didanosine (ddI) as a function of pH and time at 37° C.
  • the present invention concerns an improvement in oral dosage formulations of acid-labile dideoxy purine nucleoside derivatives, e.g. ddA, ddI, and ddG.
  • This formulation improvement concerns incorporation of the active drug ingredient in a reduced mass acid buffer formulation which can be provided as convenient palatable tablets that can be chewed and swallowed or easily dispersed in appropriate non-acidic liquids and then ingested. Reduced mass powder formulations in sachet form are also intended.
  • the new combination antacid buffer systems have improved palatability thereby making possible the use of reduced amounts of sweetening and flavoring agents, further contributing to the reduction in formulation weight.
  • Use of the new antacid buffers also result in a lowered potential for diarrhea or constipation which commonly result from chronic administration of many antacid agents.
  • water-insoluble buffers as applied to antacid agents which may be used in the instant buffer system, include antacids which have low water solubility as well as those which are generally insoluble.
  • the combination buffer systems of this invention are, in general, comprised of mixtures of water-insoluble antacid magnesium compounds with dihydroxyaluminum alkali metal carbonates or calcium carbonate.
  • Preferred mixtures comprise about one part of a water-insoluble antacid magnesium compound in combination with about 2 to 4 parts of a dihydroxyaluminum alkali metal carbonate or with about 1.5 to 3 parts of calcium carbonate which is most preferred.
  • the water-insoluble antacid magnesium compound can be selected from magnesium carbonate, magnesium carbonate hydroxide, magnesium hydroxide, magnesium oxide, magnesium phosphate (tribasic), and magnesium trisilicate; or a combination of these to comprise the magnesium antacid component.
  • Magnesium oxide and magnesium hydroxide are preferred, with magnesium hydroxide being the most preferred compound.
  • the dihydroxyaluminum alkali metal carbonates refer chiefly to dihydroxyaluminum potassium carbonate and dihydroxyaluminum sodium carbonate, which is preferred.
  • the present invention was developed in part by employing an in vitro model of a gastric system to measure acid neutralization. While the acid neutralization capacity can be readily calculated and measured using standard titration procedures, it is the rate of neutralization and maintenance-stability of the pH value that is of paramount importance with respect to nucleosidic drug stability.
  • the range of ratios of the insoluble aluminum and calcium antacid buffer agents, such as dihydroxyaluminum alkali metal carbonate and calcium carbonate, to the insoluble magnesium antacid buffer agent also reflects a balance between the diarrhea-promoting characteristics of the magnesium component and the constipation-causing characteristics of the aluminum and calcium components. Additionally, the instant combinations provide superior acid neutralizing properties which are very important given the limited quantities of buffer that can be used due to weight restrictions for tablet formulations.
  • Another feature of the improved combination antacid buffer systems concerns the resultant gastric acidity following administration.
  • a pH of about 5 would appear to be the lower limit below which the drugs undergo rapid acid-catalyzed hydrolysis.
  • a desirable buffer system would therefore maintain the stomach pH above 5 for at least half an hour but preferably for about an hour.
  • the stomach pH not rise much above 5 in order to limit the potential for physiologic pH imbalance (alkalosis) in the gastrointestinal tract.
  • the combination antacid buffer systems of the present invention were selected initially using an acid neutralization rate test which will be described in greater detail infra. It is well known that strongly basic compounds can give rise to GI alkalosis with repeated ingestion.
  • the unique synergistic characteristics of the selected insoluble aluminum and/or calcium carbonate compounds of the new combination buffer systems are demonstrated by the results obtained when aluminum hydroxide, a widely-used antacid, was substituted for the selected aluminum/calcium component of the new buffer combinations.
  • the aluminum hydroxide-containing buffer system was inferior to the instant buffer systems as it gave increased acidic pH values when studied in an in vitro gastric secretion test, even when additional aluminum hydroxide suspension was added.
  • the use of dihydroxyaluminum sodium carbonate or calcium carbonate combined with an insoluble magnesium compound gave time extended pH values in the desired range (above pH 5 but not strongly basic) when studied in the in vitro gastric secretion system, indicative of its more efficient acid neutralization. This also demonstrates that simple neutralization equivalency will not distinguish between antacid agents insofar as the desired performance is concerned.
  • a water-soluble antacid buffer such as a phosphate or citrate salt such as sodium citrate, may also be added.
  • soluble antacid buffers would be provided in a lesser amount, generally representing less than about a quarter of the total amount of buffer. In general, only the water-insoluble buffer systems are preferred.
  • insoluble antacid buffers comprising these novel pharmaceutical compositions provide superior acid neutralization capacity while having organoleptic properties which minimize the amounts of sweetening and flavoring agents required for palatability. In this way formulation weight is kept low as only small amounts of sweetening and flavoring ingredients are necessary to meet taste acceptance.
  • the water-insoluble antacid buffers are provided at a constant level, independent of the drug dose to be incorporated in the instant pharmaceutical compositions.
  • the improved buffer systems of the new formulations reduce the total amount of antacid ingested daily (about 10 g) in prior clinical formulations to a range of about 3 to 8 g daily in the reduced mass formulations, either sachets or chewable dispersible tablets at recommended dose levels. This reduction in daily antacid intake is beneficial to the GI system.
  • the dose weight of ddI may be reduced by about 20-25% when given in the new chewable/dispersible tablet formulations compared to the old "CP" sachet form.
  • the improved oral pharmaceutical compositions of this invention contain then from about 5 to 375 mg of a 2',3'-dideoxy purine nucleoside derivative such as ddA, ddI, and ddG per tablet and from about 10 to 375 mg per sachet unit.
  • sufficient antacid buffer generally in the range of about 800 to 2800 mg, comprised of a water-insoluble antacid magnesium compound in combination with a dihydroxyaluminum alkali metal carbonate or calcium carbonate; so that adequate antacid capacity is achieved by the ingestion of two tablets or one reduced mass sachet as a per dose. Desired sweetener agent, flavor and tableting excipients may be incorporated. More detailed specification of the mixed water-insoluble antacid buffer systems as well as other ingredients that may be incorporated into these novel dideoxy nucleosidic pharmaceutical compositions is given in the specific embodiments described infra.
  • Another aspect of the present invention concerns the palatability of the oral tablet formulation.
  • the taste characteristics of the water-insoluble antacid buffers selected for use in the present invention are such that their incorporation into the present pharmaceutical compositions facilitates the objective of tablet palatability by reducing the demand for ingredients to mask the taste of the buffer system itself.
  • a sweetener component was selected which is comprised of aspartame to which sucrose or sorbital may be optionally added to enhance the palatability according to the specific antacid compounds selected for the final composition. In general, little if any sucrose is added when calcium carbonate is selected as an antacid buffer component. From about 2 to 5 parts of sucrose per part of aspartame is preferred when dihydroxyaluminum sodium carbonate is an ingredient.
  • flavoring agents also may be varied depending upon the specific antacid compounds being used. Taste tests were employed to obtain the best tasting flavored compositions. Wintergreen, orange and mandarin orange flavorings are preferred.
  • two chewable/dispersible tablets having the selected strengths of drug per tablet deemed appropriate by the attending or prescribing medical practitioner, will be chewed thoroughly either together or in rapid succession.
  • a rinse of about 4 oz. (120 ml) of non-acidic liquid such as water may also be given.
  • the two tablets may be thoroughly dispersed in at least one ounce of water and the dispersion then taken orally.
  • the aqueous dispersion can be doubled or tripled in volume by the addition of another liquid such as milk, flavored milk, or a fruit juice. These mixed dispersions may be stored for up to an hour at room temperature prior to ingestion.
  • the tablets or dispersion may be given once or twice daily and preferably be ingested on an empty stomach twice daily. This means at least 30 minutes before eating or 2 hours after eating.
  • This dosing regimen is offered as a guide to clinical use with the realization that the practice of medicine is individualized and medical practitioners may depart from this general guide according to their treatment practice with individual patients.
  • the level of drug to be administered will be that which the medical practitioner feels is appropriate for the patient being treated, taking into account severity of disease, age and condition of patient and other relevant medical parameters.
  • the improved pharmaceutical compositions developed for oral administration of the acid-labile dideoxy purine nucleosides give reduced weight dosage formulations with unexpectedly improved drug bioavailability, lower variability between patients, and with better palatability relative to prior formulations. These characteristics allow the formulation of reduced mass sachets and chewable/dispersible tablet formulations with their increased convenience and patient preference. The greater patient convenience associated with the use of oral tablets is felt to have a beneficial effect on patient compliance with their drug regimen. To patients that might have problems in chewing or swallowing, the dispersibility of the tablets is a further advantage.
  • This test was developed to determine rate and duration of acid neutralization and to measure efficiency of the formulations to maintain the desired pH. This test was performed using a USP apparatus 11 dissolution assembly (paddle method). Into the dissolution vessel, 750 mL of purified water, USP was added and equilibrated to 37° ⁇ 1° C. Into this water, a calibrated pH probe was immersed, and 4.0 mL of 1.0N HCl was added, and the paddle stirrer, set at 100 RPM, was started. The contents were allowed to stir for at least two minutes before addition of the test sample. Test samples were prepared by dissolving/dispersing the test sample in a sufficient volume of water.
  • a Harvard Infusion/Withdrawal Pump (model 940) was set up with a 30 mL syringe filled with 0.8214N HCl. The piston speed was adjusted to deliver 28 mL of solution per hour (23 mEq/hour). The test sample was added to the dissolution flask and the Harvard pump was started immediately. The solution container was rinsed with purified water, USP, and the volume was made to 972 mL. The media pH was recorded at selected time intervals over a period of one hour.
  • compositions and formulations employ ddI (generically known as Didanosine) as the representative drug member of the acid-labile nucleosides. This is because ddI has been approved for use in treating AIDS patients.
  • the other acid-labile nucleosidic drug agents e.g. ddA and ddG, could be readily substituted for ddI in the compositions and formulations.
  • the pharmaceutical compositions comprise, as a powder blend, didanosine and a buffer system which is itself comprised of an insoluble magnesium antacid compound, e.g. magnesium hydroxide, combined with either calcium carbonate or an insoluble aluminum antacid compound, e.g. dihydroxyaluminum sodium carbonate.
  • an insoluble magnesium antacid compound e.g. magnesium hydroxide
  • an insoluble aluminum antacid compound e.g. dihydroxyaluminum sodium carbonate.
  • Sweeteners, flavors, and other desirable excipients used in powder blends, as well as a water-soluble antacid, e.g. sodium citrate, may also be components.
  • These pharmaceutical compositions are then formulated into oral dosing forms such as an oral powder suspension or chewable/dispersible tablets.
  • a preferred embodiment of a didanosine powder composition for an oral suspension dosage form is prepared as follows.
  • An embodiment of a didanosine chewable/ dispersible tablet formulation is prepared as follows.
  • All ingredients are placed in a tumbling type V-blender and blended for 10 minutes.
  • the blend is then milled through Fitzmill with knives forward, using 1 B plate at medium chamber speed, and medium feed rate.
  • the milled material is blended again in tumbling type V-blender for 10 minutes.
  • the blend is slugged on twelve station Colton D3 tablet press.
  • the slugs are milled through Fitzmill with knives forward, using #4 plate at slow chamber speed, and medium feed rate.
  • the milled slugs are then passed through oscillators using 16 mesh wire screen.
  • the resulting granules are placed in a tumbling type V-blender to which calculated amount of magnesium stearate 0.0125 g/2.9875 g of granulation weight, and blended for 7 minutes. This blend is then assayed for drug potency and content uniformity (found 126 mg didanosine/ 3.0 g granulation weight and RSD of 1.0% for 10 samples with a range of 124 mg to 128 mg/3.0 g granulation weight.
  • the granulation is compacted into tablets on twelve station D3 rotary tablet press using 7/8" round, flat beveled edge punches. Tablets are compacted to hardness of 16-24 Strong Cobb Units to a target weight of 3.0 g/tablet.
  • a preferred embodiment of an aluminum, sodium and sugar free didanosine chewable/dispersible tablet formulation is prepared as follows.
  • All ingredients are placed in a tumbling V-blender and blended for 10 minutes.
  • the blend is then milled through Fitzmill with knives forward using #1 plate at medium chamber speed, and medium feed rate.
  • the milled material is blended again in tumbling type V-blender for 10 minutes.
  • the blend is slugged on single punch F-press.
  • the slugs are milled through Fitzmill with knives forward, using #4 plate at slow chamber speed, and medium feed rate.
  • the milled slugs are then passed through oscillator using 16 mesh wire screen.
  • the resulting granules are placed in a tumbling type V-blender to which calculated amount of magnesium stearate 0.01 g/1.89 g of granulation weight and blended for 10 minutes.
  • the blend is then compacted into tablets on single punch F-press using 3/4" round, flat beveled edge punches. Tablets are compacted to hardness of 18-21 strong cell units to a target weight of 1.9
  • tablet formulations have the following composition.
  • a more preferred embodiment of a didanosine chewable/dispersible tablet formulation can be prepared by appropriate modification of the procedure set forth in Example 4 to provide tablets having the following composition.
  • the rate of absorption and elimination of these three formulations were essentially the same, based on the values of TMAX, MRT(INF) and T-HALF.
  • the pharmacokinetic characteristics of didanosine remained unaltered regardless of the differences in formulation.
  • the bioavailability estimates with 90% confidence limits for the chewable tablet relative to the citrate/phosphate buffer were 124% (106-135%) for CMAX and 116% (108-125%) for AUC(INF).
  • the bioavailability estimates with 90% confidence limits for the suspension relative to the citrate/phosphate buffer were 139% (121-154%) for CMAX and 125% (117-134%) for AUC(INF). Based on the 90% confidence interval approach, the two new formulations were more bioavailable than the reference formulation, citrate/phosphate buffer.
  • microcrystalline cellulose and sorbitol As the tablet potency is increased with added didanosine, an equal reduction in the combined weight of microcrystalline cellulose and sorbitol is made to adjust for constant tablet weight.
  • the ratio of microcrystalline cellulose to sorbitol is kept at a 2:1 ratio for all tablet strengths.
  • Didanosine (2,3-dideoxyinosine, dideoxyinosine, ddI) is an antiviral compound which demonstrates activity against the human immunodeficiency virus (HIV).
  • HIV human immunodeficiency virus
  • This compound is presently indicated as a clinical agent for the treatment of Acquired Immune Deficiency Syndrome (AIDS).
  • AIDS Acquired Immune Deficiency Syndrome
  • This compound is highly acid labile, but is quite stable in an alkaline environment ⁇ e.g., t 90 (time period in which 90% of drug disappears) at 37° C. is ⁇ 2 minutes at pH ⁇ 3, 16 days at pH 7.4, and 509 days at pH 9.5 (1-3) ⁇ .
  • didanosine had been available previously in the form of a lyophilized intravenous dosage form, an oral dosage form is preferred for long-term therapy.
  • the acid labile nature of the didanosine bulk drug requires that the developed oral dosage form protect didanosine from acid degradation in the stomach after oral administration.
  • the required degree of protection depends on the amount of residual acid in the stomach, the acid secretion rate, the gastric emptying rate for the dosage form, and the minimum gastric pH for acceptable didanosine stability.
  • Table 2 summarizes literature reporting human adult gastric secretion characteristics. These data suggest that the selected formulation should be capable of neutralizing a minimum of 27 mEq acid in an hour, assuming that the drug is administered on an empty stomach.
  • the ideal buffer should maintain stomach pH above 5 for approximately one hour. However, the developed buffer should not raise the stomach pH much above 5, so as not to create a physiological pH imbalance in the gastrointestinal tract.

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US20010051188A1 (en) * 1998-05-22 2001-12-13 Ismat Ullah High drug load acid labile pharmaceutical composition
WO2002013781A1 (en) * 2000-08-14 2002-02-21 Fertin Pharma A/S Method for preparation of chewing gum with customer acceptable taste
US6887926B1 (en) 2001-11-16 2005-05-03 Oatey Co. Bonding compositions for chlorinated polymers and methods of using the same
US20080299227A1 (en) * 2007-05-30 2008-12-04 Sunhealth Therapies, Inc. Method for removal of HIV from the gastrointestinal tract and bile of HIV-infected subjects and for the prevention of drug failure and prevention of development of AIDS in HIV-infected subjects
WO2013116477A1 (en) * 2012-02-02 2013-08-08 Glaxosmithkline Llc Antacid tablet

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US6887926B1 (en) 2001-11-16 2005-05-03 Oatey Co. Bonding compositions for chlorinated polymers and methods of using the same
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